tbuckley/cabot-search huggingface dataset:
Neo-adjuvant PARP inhibition prior to prostatectomy: A phase II biomarker-driven trial for men with high-risk, localized prostate cancer and alterations in DNA repair genes.
Authors: Marc Dall'era, John McPherson, Christopher P. Evans, Mamta Parikh, Rashmi Verma, Primo N Lara
Journal: Journal of Clinical Oncology (2023)

TPS401 Background: Many men with localized prostate cancer will experience recurrence and progression after radical prostatectomy. While radiation therapy for high-risk prostate cancer is routinely given with systemic androgen therapy, peri-operative systemic therapy is not part of the standard of care with prostatectomy. Defective DNA repair pathways represent a non-hormonal target for PARP inhibitors which have proven efficacy in the metastatic, castrate resistant setting. We designed a novel biomarker driven neoadjuvant trial with niraparib prior to prostatectomy for men with clinically localized high risk prostate cancer and alterations in DNA repair genes (NCT04030559). Methods: We instituted a phase II trial for men with NCCN high and very high-risk prostate cancer. All men who met inclusion by clinical variables underwent targeted genomic sequencing for somatic and/or germline alterations in genes involved in DNA repair pathways. Enrolled patients are treated with oral Niraparib 300mg/day for 90 days before surgery. The primary endpoint is pathologic response at prostatectomy defined as complete response or minimal residual disease (&lt;0.5 cc 3 ) of histological viable cancer. The secondary endpoint is biochemical free survival as well as molecular endpoints including disease responses stratified by mutational status. We have screened 37 men and 10 have met genomic criteria. We have enrolled 8 out of planned 30 men to date, 7 have undergone prostatectomy. Enrolled men have alterations in BRCA2 (germline), MSH6, ZMYM3, MUTYH, ATM, CDK12, ERCC3 and KMT2c. Clinical trial information: NCT04030559 .
First look at the baseline characteristics of participants in IRONMAN, the international registry for men with advanced prostate cancer.
Authors: Lorelei A Mucci, Jake Vinson, Travis A. Gerke, Terry Hyslop, Lauren Howard, Robert Dreicer, Dana E. Rathkopf, Kim N. Chi, Emilio Esteban, Deborah Enting, Anders Bjartell, Scott T. Tagawa, David M. Nanus, Michael Ong, Pedro C. Barata, Sebastien J. Hotte, Marie Grant, Paul Villanti, Philip W. Kantoff, Daniel J. George
Journal: Journal of Clinical Oncology (2023)

85 Background: Patients with advanced prostate cancer (APC) experience high mortality and increasingly deteriorating quality of life due to the disease itself and the therapies they are treated with. Despite recent advances in the treatment landscape, disparities in outcomes have only worsened. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease in diverse populations. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to address these needs. Methods: IRONMAN is a prospective registry initiated in 2017 with a planned accrual of 5000 patients with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer. As of 10/11/2022, 2890 patients have enrolled from 14 countries at 113 sites, with 2 more countries pending activation. Sites were selected to create a diverse cohort across race/ethnicity, geography and socioeconomic factors. Patients are followed for survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). This analysis includes patients with treatment data reported from Baseline through Month 3 as of October 2021 (n=1931, 9 countries). Results: Patients were recruited across the USA (N=799), Australia (146), Canada (282), Spain (238), England (205), and all other countries (261). 61% had mHSPC, and 39% had CRPC at enrollment with little variation in these proportions across countries. Based on self-report, 87% of patients were White, 9% Black, 4% reported other races/ethnicities, and 353 did not report race. In the US, 18% of patients were Black. Globally, 22% of respondents reported current or former military service. The most common first systemic therapy on study was androgen receptor signaling inhibitors (ARSI) +/- ADT in 1039 (54%), ranging between 12% and 66% of patients by country. 19% received chemotherapy +/- ADT and 18% received ADT alone. ARSI use varied by age, race, and metastatic disease site. Conclusions: Our preliminary results highlight our ability to successfully enroll and follow APC patients from 113 sites across 14 countries, with 2890 of 5000 planned patients enrolled. Accrual is greater in de novo mHSPC patients than anticipated. Differences in treatment patterns are already emerging, with more ARSI use in the mHSPC setting in North America than other regions. Our data demonstrates that IRONMAN participating sites are rapidly adopting new treatment recommendations into clinical practice of real-world patients.
Activity and tolerability of maintenance avelumab (AVE) immunotherapy after first-line platinum-based polychemotherapy in patients (pts) with locally advanced or metastatic squamous cell penile carcinoma: Initial results of PULSE study.
Authors: Antoine Thiery-Vuillemin, Sophie Tartas, Loic Mourey, Emeline Colomba, Delphine Borchiellini, Morgan Goujon, Felix Lefort, Delphine Topart, Philippe Barthelemy, Geraldine Lauridant, Aurelia Meurisse, Dewi Vernerey, Vincent Massard
Journal: Journal of Clinical Oncology (2023)

8 Background: Metastatic squamous cell penile carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months (mo), respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods: PULSE is a national prospective multicenter open label single arm phase II trial. Thirty-two pts will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Pts will receive AVE injections 10mg/kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) from AVE initiation according to RECIST v1.1 criteria. Key secondary endpoints will include, overall survival, safety. Here we report the results of the first interim analysis (IA). Results: From September 2019 to October 2022, 14 pts has been enrolled. Within the 9 first patients involved for the IA the median age was 69.9 years; 89% of pts had an ECOG 0-1. Of them, 1 patient and 8 pts had stage 3 and 4 disease at chemotherapy initiation, respectively. Median follow-up was 5.8 [2.3-17.2] mo. Chemotherapy regimens were triplets for 5 pts (56%), containing cisplatin for 56% and a taxane for all pts. Median duration of chemotherapy was 3.7 mo [1.2; 11.7]. At AVE initiation, 5 pts (56%) had partial or complete response and 4 pts (44%) had stable disease. Median duration of AVE was 3.7 mo with a majority (83%) of discontinuation linked to disease progression. Survival data are shown in the table. No new safety signal was identified. Conclusions: PULSE is the first prospective trial exploring avelumab maintenance activity in mSCPC. After the IA the DSMB have recommended to pursue the study based on these promising results. Updated results with additional patients, longer follow-up and ancillary explorations with biomarkers analysis will be presented at the meeting. Clinical trial information: NCT03774901 . [Table: see text]
Survival and hemoglobin A1c in metastatic castrate resistant prostate cancer.
Authors: Srinivas Govindan, Nina Cheranda, Suhong Luo, Forest Riekhof, Martin W. Schoen
Journal: Journal of Clinical Oncology (2023)

75 Background: The two common therapies for metastatic castrate resistant prostate cancer (mCRPC), enzalutamide (ENZ) and abiraterone (AA), have different effectiveness in patients with diabetes mellitus and obesity due to different mechanisms of action, along with AA requiring the co-administration of prednisone. However, no prior study has assessed responses to treatment based on glycated hemoglobin (HbA1c) while accounting for body-mass index (BMI). Methods: Patients treated with AA or ENZ from September 10, 2014 to June 2, 2017 were identified within the Veterans Health Administration. The patients were classified by most recent HbA1c values (&lt;5.6%, 5.6%-6.4%, 6.5%-7.1%, ≥7.2%) collected prior to the start of AA or ENZ. Kaplan Meier and Cox proportional hazards modeling was performed to assess the association between overall survival and covariates including age, Charlson Comorbidity Index, BMI, baseline PSA, and HbA1c. Results: 3421 veterans treated with AA or ENZ had HbA1c data available. 658 patients with HbA1c &lt;5.6%, 1430 with 5.6-6.4%, 667 with 6.5%-7.1%, and 666 with HbA1c ≥7.2. Kaplan Meier analysis showed the following median survival in months with ENZ vs AA: &lt;5.6% = 22.1 vs 24.5 (p = 0.04 by log-rank), 5.6%-6.4% = 27.7 vs 22.6 (p = 0.01), 6.5%-7.1% = 23.0 vs 19.8 (p = 0.005), ≥7.2% = 26.0 vs 21.0 (p = 0.04). Cox models showed no difference in median survival between ENZ vs AA in patients with HbA1c &lt;5.6%, adjusted hazard ratio (aHR) 1.15 (95% CI, 0.960-1.370). However, there was significantly longer survival in patients who received ENZ compared to AA in all other groups as follows: 5.6%-6.4% aHR 0.86 (95% CI, 0.759-0.965), 6.5%-7.1% aHR 0.74 (0.623-0.879) and ≥7.2% aHR 0.80 (0.669-0.948). Additionally, in patients treated with AA, higher HbA1c values were associated with inferior survival compared to HbA1c &lt;5.6%, aHR 1.40 (1.19-1.65) for 6.5-7.1% and aHR 1.25 (1.05-1.48) for ≥7.2%. Conclusions: In patients with HbA1c ≥5.6%, ENZ was associated with longer overall survival compared to AA, even when including baseline BMI. Additionally, in patients treated with AA, higher HbA1c values had inferior survivals compared to patients with HbA1c &lt;5.6%. No difference in survival was observed across the HbA1c strata with ENZ. Further studies of interactions between patient factors and treatments are warranted to guide treatment selection for prostate cancer therapy.
Sexual function after primary external beam radiation therapy (EBRT) for prostate cancer in a large cohort of men with long-term follow-up.
Authors: Domenique Escobar, Lufan Wang, Jasmin Banton, Janet E. Cowan, Samuel L. Washington, Osama Mohamad, Peter Carroll
Journal: Journal of Clinical Oncology (2023)

346 Background: Clinically localized prostate cancer can be treated with prostatectomy, radiation or focal therapy, with known impacts on sexual function. We sought to characterize long term sexual function in a large cohort of men treated with primary EBRT and to differentiate between those who have high vs low sexual function scores at baseline. Methods: Patients enrolled in CaPSURE, a national registry of men diagnosed with prostate cancer, from 1995 - 2017 with clinically localized prostate cancer (cN0M0/X, PSA &lt; = 50) and treated with primary EBRT were included. Sexual function (SF) was self-reported using the UCLA Prostate Cancer Index (PCI). We performed repeated measures mixed models to evaluate SF after EBRT, stratified by baseline SF and adjusted for age, BMI, comorbidities, smoking, clinical risk, receipt of brachytherapy and/or hormonal therapy, and type of clinical site. Results: 1193 patients were included for analysis. Mean age was 70, mean number of comorbidities was 2, and median PSA was 7.5 at diagnosis. Baseline PCI scores were available for 43% of the cohort (data not collected before 1998). The mean PCI score was 38 out of 100 at baseline and after EBRT, declined gradually to 16 by 10 years. When only those men with good SF at baseline were assessed (scores 80 – 100), the initial rate of decline was more severe, but the nadir in this group was higher than those with lower baseline scores. Unadjusted mean PCI scores showed a similar decline amongst both groups, although those with good baseline SF consistently had better scores. 63% of patients were treated for erectile dysfunction (PDE5 inhibitors, intracavernosal injections or both), 13% of whom started therapy before EBRT. In the repeated measures mixed models analysis, we found that SF changed significantly over time and scores differed significantly by age, comorbidities, baseline SF, receipt of brachytherapy boost and concurrent ADT. Conclusions: SF after EBRT declines and persists. The most affected are those who had better PCI scores at baseline, although their overall PCI scores are consistently higher compared to those with baseline scores less than 80. Among both groups however, there was a similar decline that was statistically significant.
Changes in planned disease management after piflufolastat F<sup>18</sup> PET/CT in men with biochemically recurrent prostate cancer and low PSA levels: A secondary analysis of results from the CONDOR study.
Authors: Frederic Pouliot, Michael A. Gorin, Steven P. Rowe, Lawrence Saperstein, Bela Stephen Denes, Vincent A. DiPippo, Nancy Stambler, Michael J. Morris, Barry A. Siegel
Journal: Journal of Clinical Oncology (2023)

61 Background: Piflufolastat F 18 is a PSMA-targeted radiopharmaceutical approved in the US for imaging prostate cancer (PCa) patients both at the time of initial staging and at disease recurrence. In a phase 3 study of patients with biochemically recurrent (BCR) PCa, we reported that nearly two-thirds (63.9%; 131/205) of participants had a change in their intended disease management plan based on pre- and post-piflulfolastat F 18 PET/CT management questionnaires (MMQs) completed by the treating physicians. The clinical utility of piflufolastat F 18 scanning in men with very low/low PSA levels (&lt;0.5 ng/mL) and a detection rate of ~36% has not been previously described. Here we report the changes in intended management in this subset of patients. Methods: Men ≥18 years of age with a rising PSA after definitive PCa therapy and negative or equivocal imaging were enrolled. A single ~9 mCi (333 MBq) dose of piflufolastat F 18 was administered followed by PET/CT from mid-thigh through skull vertex 1-2 hours later. Prior to scanning, the treating physicians completed a pre-PET MMQ to document the initial intended management plan for their patients based on available clinical information including baseline conventional imaging results. After PET, they completed a post-PET MMQ and recorded the management plan in light of PET findings. Treatment recommendations that differed from the pre-scan recommendations were reported as changes in the intended management plan. Results: 208 men (median PSA 0.8 ng/mL [range 0.17-98.45], n=202) underwent piflufolastat F 18-PET/CT. 200 evaluable patients had both a baseline PSA value and completed MMQs. Of 131 patients with a recorded change in intended management, 127 had an evaluable baseline PSA level. Of the 69 patients with baseline PSA levels ≤0.5ng/mL, 27 (39.1%) recorded a change in intended disease management based on positive (n=20) or negative (n=7) PET, including salvage local to systemic therapy (n=15); systemic to local therapy (n=3); observation to treatment (n=5); and treatment to observation (n=4). An additional 15 patients (21.7%) had recommended bidirectional change in management (e.g., salvage RT+ADT) and are excluded in this report. Specific treatment intensification/de-intensification plans are under investigation. Conclusions: The frequency of changes in intended disease management observed in BCR PCa patients with low baseline PSA levels (≤0.5ng/mL) was 39.1%. Both negative and positive PET/CT results impacted treatment recommendations and can provide useful and actionable information. Clinical trial information: NCT02981368 .
Characterization and impact of Wnt5A signaling on outcomes of urothelial carcinoma.
Authors: Amirali Salmasi, Harris Krause, Andrew Elliott, Alex Patrick Farrell, Emmanuel S. Antonarakis, Bruno R. Bastos, Elisabeth I. Heath, Christina Jamieson, Tyler F. Stewart, Aditya Bagrodia, Chadi Nabhan, Matthew James Oberley, W. Michael Korn, Rana R. McKay
Journal: Journal of Clinical Oncology (2023)

560 Background: Active Wnt signaling via WNT5A through ROR1 and its partner, ROR2, or WNT5A/frizzled 2 (FZD2) is linked to processes driving tumorigenesis, disease progression and therapy resistance. The role of this pathway in the pathogenesis of urothelial carcinoma (UC) is not fully elucidated. In adult tissue, ROR1 is largely absent, which makes it ideal for targeted therapies, with several ROR1 targeting agents in early clinical development. We utilized a large dataset of molecularly characterized UC tumors to investigate the significance of Wnt5a/ ROR1, ROR2 or FZD2 transcriptional expression. Methods: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 expression (SP142; Positive (+): ³2+, ³%5) was tested by IHC. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed; Bao, 2020). WNT5a, ROR1, ROR2, and FZD2-high and -low expression were defined as ³ top and &lt; bottom quartile of transcripts per million (TPM), respectively. Mann-Whitney U and X 2 /Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( q &lt; .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan Meier estimates were calculated for molecularly defined cohorts. Results: We observed similar expression of these WNT5A signaling pathway genes between upper (N=795) and lower tract UC (N=3,204): WNT5A (22.7 v. 22.2 median TMP (mTPM), q = .18), FZD2 (3.4 v 3.5, q = .93), ROR1 (2.0 v. 1.7, q = .05), and ROR2 (2.1 v 2.5, q &lt; .01). WNT family gene expression varied significantly between primary (N=2,756) and metastatic sites (N=1,361): WTN5A (25.2 v 16.8 mTPM), FZD2 (3.2 v 4.05), ROR1 (1.7 v 2.1), and ROR2 (2.4 v 2.6) for primary vs. metastatic sites respectively ( q &lt; .05 for all). Comparison of high- and low-expression subgroups revealed variation in the prevalence of TP53, FGFR3 and RB1 mutations, as well as PDL1+ staining and T cell-inflamed scores (Table). High gene expression for ROR2 (HR 0.66, 95% CI 0.56-0.78, p &lt; .001) and FZD2 (HR 0.75, 95% CI 0.63-0.89, p &lt; .001) was associated with worse OS compared to low gene expression. No significant difference in OS was observed for WNT5A (HR 0.97, 95% CI 0.82-1.15, p &lt; .76) and ROR1 (HR 0.86, 95% CI 0.72-1.01, p &lt; .068). Conclusions: Distinct genomic and immune landscapes for the four investigated WNT pathway components were observed and should be leveraged to identify combination therapies that complement the current pipeline of WNT pathway-targeting drugs. [Table: see text]
Characterization of the tumor transcriptomic differences by smoking history in locally advanced or metastatic urothelial carcinoma (UC).
Authors: Kamal Kant Kant Sahu, Nishita Tripathi, Beverly Chigarira, Nicolas Sayegh, Vinay Mathew Thomas, Haoran Li, Yeonjung Jo, Georges Gebrael, Puja Iyer, Roberto Nussenzveig, Neeraj Agarwal, Benjamin L. Maughan, Sumati Gupta, Umang Swami
Journal: Journal of Clinical Oncology (2023)

561 Background: Understanding the influences of cigarette smoke exposure at the gene expression level may have clinical significance and therapeutic implications. Investigating variations in the gene expression patterns could provide insights into differences in disease progression, survival, and therapeutic response based on smoking history amongst smokers vs. non-smokers (PMID: 29050337). Our objective was to correlate smoking with the gene expression of pts with locally advanced or metastatic UC. Methods: In this IRB-approved retrospective study, eligibility criteria included pts with locally advanced or metastatic UC with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on smoking history. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance was predetermined at p &lt; 0.05. Results: 38 pts were eligible and included: Smokers (n=18) and non-smokers (n=20). The median age at diagnosis for smokers vs. non-smokers (67 vs.71 years). The three most upregulated significant pathways amongst smokers (vs. non-smokers) were the MYC, E2F target, and cholesterol homeostasis pathways (q for all &lt;0.01) [Table]. The three most downregulated significant pathways were interferon-alpha, interferon-gamma, and inflammatory response pathways (q for all &lt;0.01). Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with advanced UC with smoking history demonstrated a different transcriptomic profile than those without smoking. Increased expression of proto-oncogene MYC and E2F could explain an aggressive disease amongst smokers. Future trials could utilize these transcriptomic differences by smoking history in guiding drug development. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with UC. [Table: see text]